Tissue/organ hypoxia impacts on the progression and outcome of a variety of human disorders, whereas environmental hypoxia threatens the life of healthy individuals, such as high altitude sojourners. We have recently discovered a novel protective mechanism in unacclimatized mice that significantly prolongs survival of these animals when exposed to lethal hypoxia. The robust protection was induced by a simple procedure of whole-body hypoxic preconditioning (WHPC), became effective shortly after the induction, and was accompanied by improved organ functions in the lung, including reduced lung cytotoxicity, vascular permeability and pulmonary edema, and ameliorated gas-exchange function. Further, we found that the lung consumed lactate under both normoxic and hypoxic conditions and that WHPC enhanced the uptake and metabolism of lactate in the lung. This enhancement appeared to depend on the upregulation of monocarboxylate transporter 2 (MCT2), a member of the transporter gene family responsible for lactate movement across the cellular and the mitochondrial membranes. We therefore hypothesize that WHPC protects the entire organism against hypoxia by improving organ functions in the lung and that the latter results from enhanced capacity of the lactate-metabolism machinery in this organ. To test this hypothesis, we will (1) characterize the beneficial effect of WHPC on cellular integrity by measuring overall cytotoxicity markers and cell-specific markers for endothelial and epithelial cells. We will also examine whether the beneficial effect of WHPC on cellular integrity is correlated with tissue ATP content in the lung; (2) determine the role of lactate in energy metabolism in the lung by exploring lactate and glucose kinetics in the lung under normoxic and hypoxic conditions, with or without WHPC. We will also examine whether disruption of lactate metabolic pathway attenuates the protective effects of WHPC; (3) delineate temporal expression patterns of MCT2 under normoxic and hypoxic conditions, with or without WHPC pretreatment We will also delineate spatial expression patterns of MCT2 at the cellular and the subcellular levels; and (4) establish a cause-effect relationship between the upregulation of MCT2 and the protection afforded by WHPC by examining whether inhibition of MCT2 using pharmacological agents and siRNA-mediated gene silencing attenuates the protective effects of WHPC and whether overexpression of MCT2 in a transgenic mouse model mimics the protective effects of WHPC. Insights into the cellular and molecular basis of WHPC will underpin future efforts for exploiting this protective mechanism for therapeutic purposes.